Oral water soluble pharmaceutical compositions containing estrone compound and calcium salt

ABSTRACT

Oral water-soluble pharmaceutical compositions containing a therapeutically effective amount of a water-soluble and stable estrogen compound such as estropipate (piperazine estrone sulfate), and at least one water-soluble, pharmaceutically acceptable calcium salt in the presence of a suitable, pharmaceutically acceptable excipient. Compositions which include an organic acid and a calcium carbonate or bicarbonate compound which reacts with the organic acid when the composition is added to water to provide effervescence are preferred.

This application is a 371 of PCT/EP94/02465 filed Jul. 26, 1994.

TECHNICAL FIELD

The present invention relates to oral water soluble pharmaceuticalcompositions containing estrone derivative, useful for the substitutivehormonal therapy (hypoestrogenic) and in the prevention of the bone lossin the cases of senile or post-menopausal osteoporosis.

BACKGROUND ART

Estrone, the metabolite of estradiol, is used alone or in combinationwith other natural estrogens, in the form of ester (acetate, propionate)or as hydrosoluble conjugate (sodium or piperazine sulphate) in thesubstitutive hormonal therapy (hypoestrogenic) and in the prevention ofthe bone loss in the cases of post-menopausal Osteoporosis or inoophorectomized women.

The administration of estrone at therapeutical doses is effected both byoral route (tablets) and parenteral or transdermal route.

Estrogens are usually administered as oral tablets, the most commonpreparations being conjugated (equine) estrogens, micronized estradiol,and estrone piperazine sulfate (estropipate).

The oral administration of liquid compositions containing estronepresents some difficulties due to the insolubility in water of thecompound, as well as of its esters. This problem can be solved byformulating the medicament in solid oral forms, but the problem of theincomplete absorption of the active ingredient at gastric level and ofthe possible difficulty of administering said forms to patients withpoor swallowing capacity still remains.

It is well known that oral water soluble, liquid and optionallyeffervescent forms promote the absorption of the active ingredient, asfor example in the case of aspirin, paracetamol, potassium, and others.Moreover, the liquid effervescent formulations result particularlyappreciated to patients in view of their aspect and the possibility togive them good palatability.

For the preparation of liquid forms comprising estrone it is necessaryto provide their hydrosoluble compounds. The alkali-conjugate estronesalts (sodium-sulfates) are hydrosoluble, but unstable in aqueous media,with the resulting precipitation of insoluble products.

In the bone-loss preventive therapy it is common practice to provide acalcium supplement to the patient. A large number of calciumpreparations are available, including chewable tablets, ordinary oraltablets and even effervescent preparations.

The oral absorption of these available preparations is deemed to besatisfactory, although it can be variable depending on the nature of thecalcium salt (carbonate, citrate, gluconate, lactate, phosphate, etc.).An extensive description of available calcium preparations can be foundin the 3^(rd) edition of Martindale, The Extra Pharmacopoeia, London,The Pharmaceutical Press, 1993, page 853 to 856.

If the skilled technician had thought to combine an estrogen derivativewith a calcium salt in an oral, liquid composition, he would have facedsome critical issues of pharmaceutical technology and pharmacology.

The estrogen component must be freely soluble in aqueous concentratedelectrolyte solutions and stable, at neutral or basic pH, if theresulting pH of the liquid preparation is acidic, the estrogen componentmust be stable in a conjugate form (acid sulfate) even if present as afinely dispersed colloidal form, readily absorbed at intestinal pH.

The calcium preparations must be readily soluble in water giving asolution which should be clear or slightly cloudy but without insolubleresidues, which, if formed, will not be completely absorbed.

The combination tablet or sachet must be pharmaceutically stable,particularly concerning the estrogen component and have an acceptableshelf-life.

The tablet or sachet must dissolve in water within a conveniently shorttime, preferably within a few minutes, to avoid hydrolysis of theestrogen component or precipitation of the calcium salts out of thesaturated aqueous solution.

If needed, the effervescence during dissolution of the preparationshould be moderate to avoid spraying the saturated solution on the wallof the container and therefore depositing an insoluble rim which couldtake the crucial estrogen component out of solution.

The ingredients of the formulation must not interfere with the accuracyof the analytical determination of the estrogen component which ispresent in very small amounts. In addition the final pH of the solutionshould be very close to 7 since higher pHs favour the precipitation ofthe calcium ingredient as calcium hydroxide and lower pHs will hydrolizethe estrogen conjugate and give the less absorbable free estrone.

Finally, the preparation must have an acceptable or a pleasant taste foroptimal patient compliance.

As far as the applicant is aware, there is no teaching in the prior arton how to solve all the above problems.

SUMMARY OF THE INVENTION

After a thorough experimentation, it has now surprisingly been foundthat the association between a water soluble and stable estrogenderivative and a pharmaceutically acceptable soluble salt of calciumallows the preparation of acceptable liquid and, if needed, effervescentpharmaceutical compositions which ensure a good absorption of the activeingredient when orally administered.

Therefore the object of the present invention are oral water solublepharmaceutical compositions characterized in that they contain acombination of a water soluble and stable estrogen derivative and atleast one soluble salt of calcium. Preferably, the compositions providedby the present invention are in the form of oral water solubleeffervescent composition.

Said compositions, once added to a suitable amount of water, givecomplete drinkable solution within minutes.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Advantageously, the presence of calcium ions in the compositionsaccording to the invention yields a further therapeutical support to theaction of estrone in the treatment of senile or post-menopausalosteoporosis. A further advantage of the present invention is to providein a single pharmaceutical composition a twofold therapeutic action, theestrogenic one and the mineral one. A still further advantage of thepresent invention is to provide a drinkable solution, which ensures theoptimal oral absorption of the active ingredients, at the same timeproviding a good compliance by the patient, especially by elder peoplehaving swallowing difficulties. Lastly, the present invention provides apharmaceutical composition with a reduced cost of medication.

In a preferred embodiment of the invention calcium hydrogencarbonate isthe calcium salt.

In a more preferred embodiment, calcium carbonate is the calcium salt.

In a even more preferred embodiment of the present invention, calciumglycerophosphate is the calcium salt. This last is preferred for itswater solubility and high elemental calcium content and is also capableof providing a desiderable amount of phosphorus.

In a most preferred embodiment, estropipate is the estrogen derivative.

Estropipate has proved to be the most suitable estrogen derivativebecause of its water solubility and stability, contrarily to the muchless stable conjugate equine estrogens or the insoluble non-conjugatedestrogen preparations. It is however clear that other stable andsuitable estrogen conjugates can be used such as the ammonium andsubstituted ammonium salts such as the tromethamine salt, the solublesuccinate salts, the phosphate ester salts and similar pharmaceuticallyacceptable soluble derivatives well known to the skilled in the art.

The compositions of the present invention can be in the form ofgranulate or tablets.

Said compositions are prepared according to conventional techniques wellknown to the expert in the field, as de scribed for example in"Remington's Pharmaceutical Sciences Handbook" XVII Ed.; Mack pub.U.S.A..

As known, effervescence is obtained by means of a reaction in aqueousambient between an acid and a carbonate or a bicarbonate.

The mostly used acids are citric, tartaric, fumaric and boric acid.Citric, tartaric and fumaric acid, particularly citric acid, whichcontributes to give an agreeable taste to the final solution, arepreferred.

Among the carbonates usable according to the invention, those of sodium,potassium, lithium and calcium can be cited.

Calcium carbonate is more preferred, since it contemporaneously yieldsthe calcium provided in the present invention and the source of CO₂necessary for effervescence.

Whenever the expert in the field considered useful to use suitableexcipients, such as binders, lubricants, sweetenings, aromatizing, dyes,this can be done however without departing from the scope of the presentinvention.

Examples of binders are sugars, glycine.

Examples of lubricants are benzoates, polyethylene glycols, leucine.

The process for the preparation of the compositions of the presentinventions provides the work up in suitable conditions which avoids theearly reaction between the acid and carbonate, in particular lowhumidity (35% maximum) and temperature (25° C. maximum) shall becontrolled.

The pharmaceutical compositions according to the invention may be in theform of powders, granules, sachets, tablets, or in the form of liquidcompositions, such as solutions.

Although the dosages are determined by the pathology kind, theconditions of the patient (age, sex, weight) and will be established bythe skilled doctor, a dose range is indicated from 0.375 to 1.50 mg(corresponding to 0.3125 to 1.25 mg of sodium estrone sulfate).

The ratios among estropipate, calcium salt and other excipients whichconcur in the formulation of the soluble or effervescent compositionsaccording to the present invention are not critical. In particular,estropipate and the calcium salt will be contained in the form of dosageunit in a therapeutically effective amount, whereas the expert in thefield will easily be capable of determining the ratio between the acidand the carbonate, or bicarbonate, as to assure a good effervescence andrapid dissolution of the pharmaceutical composition.

EXAMPLES

The following examples further illustrate the present invention.

Example 1

For 10,000 effervescent tablets the following ingredients were used:

17.22 kg of granular calcium carbonate

5.20 kg of granular citric acid

3.05 kg of granular fumaric acid

7.50 g of estropipate (estrone sulphate of piperazine 1:1)

1.00 kg of leucine hydrochloride

50 g of soluble flavours

50 g of calcium ciclamate.

The ingredients were put in a mixer (P-K twin-shell blender, or thelike) and mixed for 20 minutes. The mixture was tabletted, granulatedand sieved (16 mesh).

The sieved granulate was tabletted in an atmosphere with less than 30%of humidity at the temperature of 20° C. to give 10,000 effervescenttablets.

The above amounts can be modified according to the desired posology ofestrone or elemental calcium, by varying, if necessary also the amountof citric acid necessary for effervescence.

Example 2

For 10,000 effervescent tablets the following ingredients were used:

52.50 kg of calcium glycerophosphate

22.30 kg of saccharose

1.00 kg of PEG 6000

7.50 g of estropipate (estrone sulphate of piperazine 1:1)

0.10 kg of silicon dioxide

0.10 kg of magnesium stearate

1.50 kg of leucine

1.70 kg of citric acid

5.00 kg of aspartame

5.00 kg of sodium bicarbonate.

The ingredients were worked according to the procedure of Example 1 togive 10,000 effervescent tablets.

Example 3

10,000 non effervescent sachets were prepared with the ingredients shownin Example 2, except silicon dioxide and magnesium stearate, citric acidand sodium bicarbonate.

Example 4

Oral liquid pharmaceutical compositions were prepared according toconventional techniques with the following unitary composition:

    ______________________________________                                        Calcium glycerophosphate                                                                         5.250      g                                               Saccharose         2.230      g                                               PEG 6000           0.100      g                                               Estropipate        0.750      mg                                              Leucine            0.150      g                                               Aspartame          0.050      mg                                              Distilled water    100        g.                                              ______________________________________                                    

Example 5

Oral effervescent pharmaceutical compositions were prepared according tothe above examples with the following unitary composition:

    ______________________________________                                        Estropitate      0.75         mg                                              Ca glycerophosphate                                                                            5.250        g                                               Citric acid      0.5          g                                               Sodium bicarbonate                                                                             0.658        mg                                              Sucrose          4.000        g                                               Aspartame        0.04         g                                               Aroma (orange)   0.05         g.                                              ______________________________________                                    

For all the above examples it is understood that flavouring agentscolorants and aroma can be added according to conventional practice.

The above amounts can be modified according to the desired posology ofestrone or elemental calcium, by varying, if necessary also the amountof citric acid necessary for effervescence.

What is claimed is:
 1. An oral water soluble pharmaceutical compositioncontaining a therapeutically effective amount of a water-soluble andstable estrogen compound and at least one water-soluble,pharmaceutically acceptable calcium salt of calcium glycerophosphate orcalcium hydrogen carbonate in the presence of a suitable,pharmaceutically acceptable excipient.
 2. The composition according toclaim 1, characterized in that the estrogen compound is estropipate(piperazine estrone sulfate).
 3. The composition according to claim 1,characterized in that calcium glycerophosphate is the calcium salt. 4.An oral water-soluble pharmaceutical composition containing atherapeutically effective amount of a water-soluble and stable estrogencompound, and first and second water-soluble, pharmaceuticallyacceptable calcium salts in the presence of a suitable, pharmaceuticallyacceptable excipient.
 5. The compositions according to claim 1,characterized in that calcium hydrogencarbonate is the calcium salt. 6.The composition according to claim 4, characterized in that the estrogencompound is estropipate (piperazine estrone sulfate).
 7. Aneffervescent, oral, water-soluble pharmaceutical composition containinga therapeutically effective amount of a water-soluble and stableestrogen compound and at least one water-soluble calcium salt in thepresence of a suitable, pharmaceutically acceptable excipient.
 8. Thecompositions according to claim 1 in the form of powders, granulates,tablets or a liquid.
 9. Oral effervescent pharmaceutical compositionsaccording to claim 7 in the form of tablets having the following unitarycomposition:

    ______________________________________                                        calcium glycerophosphate                                                                              5.250    g                                            saccharose              2.230    g                                            PEG 6000                0.100    g                                            estropipate (estrone sulphate of piperazine 1:1)                                                      0.750    mg                                           silicon dioxide         0.010    g                                            magnesium stearate      0.010    g                                            leucine                 0.150    g                                            citric acid             1.700    g                                            aspartame               0.050    g                                            sodium bicarbonate      0.500    g.                                           ______________________________________                                    


10. Oral effervescent pharmaceutical compositions according to claim 7in the form of tablets having the following unitary composition:

    ______________________________________                                        Calcium carbonate granular                                                                       1.722      g                                               Citric acid granular                                                                             0.520      g                                               Fumaric acid granular                                                                            0.305      g                                               Estropipate        0.750      mg                                              Leucine hydrochloride                                                                            0.10       g                                               Soluble flavours   5.0        mg                                              Calcium ciclamate  5.0        mg.                                             ______________________________________                                    


11. Oral water soluble pharmaceutical compositions according to claim 8in the form of granules or powder or sachets having the followingunitary composition:

    ______________________________________                                        Calcium glycerophosphate                                                                         5.250      g                                               Saccharose         2.230      g                                               PEG 6000           0.100      g                                               Estropipate        0.375      mg                                              Leucine            0.150      g                                               Aspartame          0.050      mg                                              ______________________________________                                    


12. Oral liquid pharmaceutical compositions according to claim 8 of thefollowing unitary composition:

    ______________________________________                                        Calcium glycerophosphate                                                                         5.250      g                                               Saccharose         2.230      g                                               PEG 6000           0.100      g                                               Estropipate        0.750      mg                                              Leucine            0.150      g                                               Aspartame          0.050      mg                                              Distilled water    100        g                                               ______________________________________                                    


13. The composition of claim 7 wherein the water soluble calcium saltcomprises an organic acid and a calcium carbonate or bicarbonatecompound which reacts with the organic acid when the composition isadded to water.
 14. The composition of claim 13 where the organic acidis citric acid, the calcium compound is calcium carbonate and theestrogen compound is estropipate (piperazine estrone sulfate).
 15. Thecomposition of claim 7 which includes an organic acid and a carbonate orbicarbonate compound which reacts with the organic acid when thecomposition is added to water to provide effervescence.
 16. Thecomposition of claim 15 wherein the organic acid is citric, tartaric orfumaric acid, the carbonate or bicarbonate compound is a sodium,potassium, lithium or calcium carbonate, and the estrogen compound isestropipate (piperazine estrone sulfate).
 17. The composition accordingto claim 7, in the form of powders, granulates, tablets or a liquid. 18.The composition according to claim 4, characterized in that calciumsalts include calcium glycerophosphate, calcium hydrogen carbonate, orthe reaction product of calcium carbonate or bicarbonate with an organicacid.
 19. The composition according to claim 4, in the form of powders,granulates, tablets or a liquid.